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KMID : 1038020200280040169
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Translational and Clinical Pharmacology
2020 Volume.28 No. 4 p.169 ~ p.174
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Predicting human pharmacokinetics from preclinical data: volume of distribution
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Yim Dong-Seok
Choi Sue-In
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Abstract
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This tutorial introduces background and methods to predict the human volume of distribution (Vd) of drugs using in vitro and animal pharmacokinetic (PK) parameters. The physiologically based PK (PBPK) method is based on the familiar equation: Vd = Vp + ∑T(VT × ktp). In this equation, Vp (plasma volume) and VT (tissue volume) are known physiological values, and ktp (tissue plasma partition coefficient) is experimentally measured. Here, the ktp may be predicted by PBPK models because it is known to be correlated with the physicochemical property of drugs and tissue composition (fraction of lipid and water). Thus, PBPK models' evolution to predict human Vd has been the efforts to find a better function giving a more accurate ktp. When animal PK parameters estimated using i.v. PK data in ≥ 3 species are available, allometric methods can also be used to predict human Vd. Unlike the PBPK method, many different models may be compared to find the best-fitting one in the allometry, a kind of empirical approach. Also, compartmental Vd parameters (e.g., Vc, Vp, and Q) can be predicted in the allometry. Although PBPK and allometric methods have long been used to predict Vd, there is no consensus on method choice. When the discrepancy between PBPK-predicted Vd and allometry-predicted Vd is huge, physiological plausibility of all input and output data (e.g., r2-value of the allometric curve) may be reviewed for careful decision making.
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KEYWORD
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Volume of Distribution, PBPK Human PK Prediction
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